The continued abuse of methamphetamine (METH) in this country is particularly troubling because of the severe persistent psychiatric symptoms and disturbing social impact of this potent psychostimulant. In order to better deal with the consequences of METH addiction, it is important to elucidate the mechanisms associated with its short- and long-term effects. Two important issues we and others have researched that are particularly germane to the present proposal are: first, the property of METH to cause persistent deficits in striatal dopamine systems (neurotoxicity) under some, but not all, conditions: and second, the related observation of a unique response to METH treatment by adolescent versus adult animals. The overall objective of this revised proposal is to elucidate the neurotoxic responses of subcortical monoamine systems to METH, as it relates to the differential vulnerability of striatal dopamine (DA) under varying refractory conditions. Thus, studies in this proposal are based on our and others'observations that factors linked to the METH-induced persistent striatal DA deficits fall into two stages based on their temporal relationship to drug exposure (i.e., Stage 1=0-8 h and Stage 2=24-72 h). We will achieve the overall objective by testing the prevailing hypothesis that "events occurring during Stage 1 followed by those of Stage 2 are necessary for the expression of METH-induced toxicity in striatal DA systems and the models of resistance to METH toxicity to be studied in this Program Project interfere with the requisite events in distinct ways." This hypothesis will be tested by examining alterations in the expressions of METH-induced Stages 1 and 2, and underlying mechanisms, in the following models of METH resistance: (i) adolescent rats (project #1- "Developmental Refractoriness," project director is Dr. Annette Fleckenstein);(ii) adult rats pretreated with a neurotoxic-METH treatment (project #2-"Lesion-induced Refractoriness in Adults," project director is Dr. Kristen Keefe);and (iii) rats previously exposed to a temporary tolerance caused by incrementally increasing METH doses (project #3-"tolerance-related Reversible Refractoriness," project director is Dr. Diana Wilkins). It is anticipated that elucidation of mechanisms for these 3 refractory models will inform issues such as: (i) adolescent drug abuse vulnerability;(ii) impact of METH use during adolescent development;and (iii) the persistent impact of METH-related neurotoxicity during adulthood. PROGRAM PROJECT CHARACTERISTICS